In this study it has been shown that major changes in solute rejection can occur when the solute is part of a multicomponent system instead of a binary system. The effect of changes in the thermodynamic activity of the solute on its rejection has been studied. As a model system the combined ultrafiltration of poly(ethylene glycol) (PEG) and dextran has been chosen. The thermodynamic activities of PEG and dextran have been modelled with the UNIQUAC model. Rejection measurements showed a decrease in the observed PEG rejection when dextran was added to the solutions under conditions where the dextran was mainly retained by the membrane. At high dextran concentrations and low fluxes the PEG rejection even became strongly negative. The PEG concentration in the permeate was at maximum a factor 2 higher than in the permeate (on a dextran-free basis). For a more open membrane the rejection of PEG was found to increase in the presence of dextran. The elevated transport of PEG through the membrane in the presence of dextran was ascribed to the additional driving force due to the increased thermodynamic activity of PEG at the retentate side of the membrane. The results in this paper show that thermodynamic interactions can have a strong impact on the observed rejection and are certainly worth being considered in multicomponent systems.